Seizure Drug Promising in Sleep Apnea
Published: Sep 11, 2013
By Crystal Phend, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Zonisamide, a seizure drug with carbonic anydrase activity, had beneficial effects on obstructive sleep apnea in a pilot study in overweight and obese adults.
BARCELONA -- The seizure drug zonisamide (Zonegran) modestly eased obstructive sleep apnea (OSA) in overweight and obese adults, a pilot trial showed.
Apnea-Hypopnea Index scores dropped by 22% among patients randomized to the drug over 4 weeks compared with a slight increase on placebo, Jan Hedner, MD, of the University of Gothenburg, Sweden, and colleagues found.
The effect was only about a third of that with continuous positive airway pressure (CPAP), but it did correlate with a marker of biological impact of the drug, the researchers reported here at the European Respiratory Society meeting.
"It's imperfect; however, I think we have a very good clue here that we can develop this further if we understand what is the target," Hedner told MedPage Today.
Pharmacologic treatment might be an option for the roughly half of patients who can't get or won't use CPAP, he suggested.
More importantly, though, the drug effect pointed to a mechanism in obstructive sleep apnea.
From that perspective, "CPAP is one of the worst events that happened in sleep medicine because it took away incentive to do research to really understand where this disease is acting," Hedner said. "CPAP is like a breathing wheelchair: You can technically treat all people but you still don't quite understand what you're treating."
Zonisamide has two potential routes to benefit in OSA: It leads to weight loss and increases breathing.
Like the anticonvulsant topiramate (Topamax), zonisamide is a carbonic anhydrase inhibitor.
Blocking the action of these enzymes that help convert carbon dioxide and water to bicarbonate, the key pH balancing component in the body, you become a bit more acidified, and acidification means more breathing in most situations," Hedner explained.
His group concluded that carbonic anhydrase inhibition "provides a potential target for development of a pharmacological remedy in OSA."
The study included 47 patients ages 18 to 75 with a body mass index between 27 and 35 kg/m2 (mean 31.2) and an Apnea-Hypopnea Index of at least 15 events per hour (mean 41.5) with daytime sleepiness.
They were randomized to zonisamide at 300 mg, CPAP, or placebo. While weight loss was expected based on prior studies with the drug, there was no diet or lifestyle counseling.
The Apnea-Hypopnea Index score dropped from 41.6 per hour at baseline to 32.9 per hour at week 4 in the zonisamide group, which was a significant mean change of -9 per hour (95% confidence interval -17 to -1).
By contrast, the placebo group had a slight increase in hypoxic events from 45.7 per hour at baseline to 49.7 per hour at week 4. While that wasn't a significant change, it was a significant difference in treatment effect versus the epilepsy drug (P=0.04).
Bicarbonate as marker of biologic activity of zonisamide showed a clear demarcation between the two, with the exception of one zonisamide patient, an outlier Hedner described as likely nonadherent to the drug.
But the bicarbonate effect didn't correlate much with change in oxygen desaturation.
"We have a definite effect," Hedner noted, but "the effect seems to be confined to a subgroup and we really need to find out what's different in these people."
Those effects were too early to have been influenced by weight loss on the drug, he added.
By 24 weeks, the zonisamide group had lost an average of 2.7 kg (6.0 lb) compared with a gain of 2.3 kg (5.1 lb) in the CPAP group.
Controlling for compliance, CPAP held a much greater benefit for sleep apnea, reducing apnea-hypopnea events by 28.3 per hour over baseline compared with 8.0 fewer events per hour with the drug at 24 weeks (P=0.004).
Most zonisamide-treated patients reported adverse events (87% versus 11% with CPAP).
Additional research is needed to show whether the drug reduces OSA-related health risks and makes patients feel better, Hedner pointed out.
A first step might be to include sleep apnea as one of the outcome variables in trials with the drug for other uses, he suggested.
Hedner reported having no relevant conflicts of interest other than a related patent.
Primary source: European Respiratory Society
Source reference: Eskandari D, et al "Zonisamide reduces obstructive sleep apnea: A randomized placebo-controlled study" ERS 2013; Abstract P4036.